U.S. patent number 4,996,222 [Application Number 07/490,851] was granted by the patent office on 1991-02-26 for pharmaceutical formulations.
This patent grant is currently assigned to Smith Kline & French Laboratories Limited. Invention is credited to Brian A. C. Carlin, John N. C. Healey, Graham S. Leonard, Geoffrey D. Tovey.
United States Patent |
4,996,222 |
Carlin , et al. |
February 26, 1991 |
**Please see images for:
( Certificate of Correction ) ** |
Pharmaceutical formulations
Abstract
The invention provides pharmaceutical suspension compositions of
cimetidine wherein substantially all of the cimetidine is in the
polymorph B crystalline form.
Inventors: |
Carlin; Brian A. C. (Baldock,
GB2), Healey; John N. C. (Hitchin, GB2),
Leonard; Graham S. (St. Albans, GB2), Tovey; Geoffrey
D. (Harpenden, GB2) |
Assignee: |
Smith Kline & French
Laboratories Limited (Welwyn Garden City, GB)
|
Family
ID: |
10602097 |
Appl.
No.: |
07/490,851 |
Filed: |
March 9, 1990 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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79198 |
Jul 29, 1987 |
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Current U.S.
Class: |
514/400 |
Current CPC
Class: |
A61P
1/00 (20180101); A61K 31/415 (20130101); A61P
1/04 (20180101); A61K 9/0095 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 31/415 (20060101); A61K
031/415 () |
Field of
Search: |
;514/400 |
Foreign Patent Documents
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138540 |
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Apr 1985 |
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EP |
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104868 |
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Aug 1981 |
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JP |
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Primary Examiner: Chaudhuri; Olik
Assistant Examiner: McAvoy; Ellen
Attorney, Agent or Firm: Dinner; Dara L. Lentz; Edward T.
Suter; Stuart R.
Parent Case Text
This is a continuation of application Ser. No. 07/079,198 filed
July 29, 1987, now abandoned.
Claims
What is claimed is:
1. A stable pharmaceutical composition suitable for oral
administration comprising a suspension of an effective histamine
H2-antagonist amount of particulate cimetidine in an aqueous phase
wherein substantially all of the cimetidine present is of the
polymorphic B form.
2. A composition according to claim 1 wherein at least 95% of the
cimetidine is in the polymorphic B form.
3. A composition according to claim 1 having a pH in the range
7-9.5.
4. A composition according to claim 1 wherein the viscosity of the
suspension, as measured at 25.degree. C. and at a shear rate of 0.7
sec.sup.-1, is in the range 200 mPa.s to 1.500 mPa.s.
5. A composition according to claim 4 wherein the viscosity is 500
mPa.s to 1.200 mPa.s.
6. A composition according to claim 1 which contains a suspending
agent.
7. A composition according to claim 6 wherein the suspending agent
is a mixture of sodium carboxymethyl-cellulose and microcrystalline
cellulose, which mixture is present in an amount in the range of
from about 0.6 to about 1.5% w/w of the total weight of the
composition.
8. A composition according to claim 1 wherein at least 80% of the
cimetidine particles have an apparent diameter in the range of from
about 5.mu. to about 200.mu..
9. A composition according to claim 1 which contains an antacid or
alginate.
10. A composition according to claim 1 containing 1.5-3.5% w/w of
cimetidine, 35-15% w/w of water, 35-55% w/w of sorbitol, 0-10% w/w
of a humectant selected from the group consisting of propylene
glycol or glycerol and 0.6-1.5% w/w of a mixture of sodium
carboxymethyl cellulose and microcrystalline cellulose.
11. A composition according to claim 9 which contains EDTA or a
salt thereof in an amount from about 0.05% w/w to about 0.1% w/w of
the total weight of the composition.
12. A composition according to claim 1 wherein at least 90% of the
cimetidine is in the polymorph B form.
13. A process for producing a stable pharmaceutical composition
comprising dispersing a suspending agent with a substantially pure
effective amount of histamine H.sub.2 antagonist Polymorph B
cimetidine into a suspension such that the viscosity of the
resulting suspension is less than 1500 mPa's and greater than 200
mPa's.
14. A stable pharmaceutical composition, which is readily pourable,
suitable for oral administration comprising a suspension of an
effective histamine H.sub.2 -antagonist amount of a particulate
cimetidine in an aqueous phase wherein substantially all of the
cimetidine present is of the polymorphic B form.
15. A composition according to claim 14 wherein the resulting
viscosity of the suspension, as measured at 25.degree. C. and at a
shear rate of 0.7 sec.sup.-1, is in the range of 200 mPa's to 1,500
mPa's.
16. A stable pharmaceutical composition suitable for oral
administration comprising an alginate, and a suspension of an
effective histamine H.sub.2 -antagonist amount of a particulate
cimetidine in an aqueous phase wherein substantially all of the
cimetidine present is of the polymorphic B form.
Description
This invention relates to new pharmaceutical compositions and
methods for their preparation, and in particular it relates to
suspensions comprising cimetidine.
Cimetidine is a histamine H.sub.2 -antagonist which has been used
for a number of years in the treatment of duodenal and benign
gastric ulceration, recurrent and stomal ulceration, oesophageal
reflux disease and other conditions where reduction of gastric acid
by cimetidine has been shown to be beneficial, for example
persistent dyspeptic symptoms with or without ulceration. It is
widely recognised that there are considerable technical
difficulties in producing stable and acceptable pharmaceutical
compositions of cimetidine, particularly liquid solution and
suspension compositions. Firstly, there is the difficulty of
polYmorphism which gives rise to problems of polYmorphic
transitions and crystal growth. It is generally recognised that
cimetidine can exist in at least 5 different polymorphic forms and
that these polymorphic forms differ in crystal habit and
crystallisation properties, thermodynamic stability, and solubility
and rate of dissolution in water. It is generally recognised that
the polymorphic form A has been used almost exclusively in
compositions. B. Hegedus and S. Gorog, J. Pharmaceutical &
Biomedical Analysis, Vol. 3, No. 4, pp.303-313, 1985. Secondly,
there is the problem that cimetidine has a very bitter taste and
palatability of oral compositions is a major consideration.
It is clear that there has been a need for compositions of
cimetidine which are liquid based and are palatable. Cimetidine is
absorbed almost exclusively in the small intestine and liquid-based
compositions offer the possibility that they could be absorbed more
quickly and more efficiently than tablet compositions, particularly
tablet compositions which have been coated to minimise unpleasant
tastes. However, with solutions of cimetidine, the unpleaSant
bitter taste is a particular problem. Suspensions of cimetidine
could in principle offer the advantage of being more palatable but
until recently no stable suspension compositions of cimetidine have
been described or sold. Some companies have tried to meet the
apparent need for such a product by selling cimetidine powder or
granules in sachets which can be extemporaneously mixed with water
to produce suspension compositions.
EPA 0 138 540-A describes suspensions containing cimetidine and the
preferred examples are buffered solutions of high viscosity.
Because of the high viscosity, such suspensions are not easily
poured from a bottle and consequently are usually formulated in
sachets.
Aqueous suspensions of cimetidine polymorph A are thermodynamically
unstable and it is found that when many such suspensions are
prepared having relatively low viscosity, they are likely, when
subjected to fluctuating temperatures, to undergo polymorphic
transition into the polymorphic B form. This polymorphic
transition, forms polymorph B in situ as very long needle-like
crystals, which makes the suspensions lumpY and non-homogeneous
thereby introducing dosage inaccuracy and giving rise to an
unpleasant mouth feel.
It is an object of this invention to provide a suspension of
cimetidine which is stable and, in particular, is of relatively low
viscosity such that it can be easily poured from bottle and easily
administered using a spoon or like device so that Various dosages
can be exactly and accurately measured. It is also an object of
this invention to form a stable composition to which other
ingredients such as antacids or alginates can be added.
We have now found that by preparing suspensions from cimetidine
polymorph B, the problem of polymorphic transition and the growth
in situ of long needle-like crystals can be avoided.
According to the invention, there is provided a stable
pharmaceutical composition suitable for oral administration
comprising a suspension of particulate cimetidine in an aqueous
phase having a pH of at least 7, and a suspending agent, wherein
substantially all of the cimetidine present is of the polymorphic B
form, and optionally any other pharmaceutical excipients.
Preferably at least 90% and particularly preferably at least 95% of
the cimetidine is in the polymorphic B form. It is preferred that
substantially no polymorph A is present.
By stable is meant a suspension which is capable of remaining in a
pharmaceutically acceptable condition for a prolonged period, for
example at least six months, preferably at least a year and most
preferably for more than three years. Thus there should not be
significant crystal growth, and any sediment formed should be
capable of being re-suspended with only mild agitation, i.e. the
sediment should not take the form of a "cake" or lumps which cannot
readily be re-suspended. Preferably no sediment should form at
all.
It is in general preferred that the pH of the suspension is within
the range 7-9.5, preferably 7.4-8.4, and particularly 7.8-8.2. It
Will be appreciated that the suspensions can be either buffered or
unbuffered.
It is preferred that the suspensions of the present invention have
a viscosity of less than 1,500 mPa.s but greater than 200 mPa.s,
for example within the range 1,200 mPa.s to 500mPa.s. The skilled
man will be aware that the viscosity values obtained for a given
system depend on the temperature, the shear rate and the shear
history. The above figures refer to freshly shaken and poured
suspensions at approximately 25.degree. C. subjected to a shear
rate of 0.7 sec..sup.-1.
An advantage of suspensions having a viscosity within the range 200
mPa.s to 1,500 mPa.s is that they are readily pourable. This is in
contrast to suspensions prepared from cimetidine polymorph A which
frequently are required to be of a high viscosity in order to
remain stable, i.e. to minimise polymorphic interconversion, the
viscosity being such that they are not readily pourable. By readily
pourable is meant that they are capable of being easily poured from
a suitable container such as a bottle. It will be readily
appreciated that where the composition is a reversible gel, it may
be necessary to shake the container before pouring in order to
disrupt the gel structure.
When the suspension contains alginate, the thickening effect of the
alginate means that the viscosity of the suspension is generally
higher than the range 200-1,500 mPa.s quoted above and typically is
in the the range 2,500-5,000 mPa.s for example approximately 3,500
mPa.s.
Examples of suspending agents include xanthan gum,
hydroxypropylmethylcellulose, methylcellulose, carageenan, sodium
carboxymethyl cellulose, and sodium carboxymethyl
cellulose/microcrystalline cellulose mixtures, particularly sodium
carboxymethyl cellulose/microcrystalline cellulose mixtures.
Preferred suspending agents are thixotropic suspending agents such
as xanthan gum, carageenan and sodium carboxymethyl
cellulose/microcrystalline cellulose mixtures and particularly
preferred suspending agents are Avicel RC591, Avicel RC581 and
Avicel CL611. Avicel is a trademark of FMC Corporation, and RC591,
RC581 and CL611 are mixtures of microcrystalline cellulose and
sodium carboxymethyl cellulose. The amount of suspendinq agent
present will vary according to the particular suspending agent used
and the presence or absence of other ingredients which have an
ability to act as a suspending agent or which contribute
significantly to the viscosity of the composition. In general,
however, the amount of suspending agent will lie in the range
0.1-1.5% w/w of the total weight of the composition. When the
suspending agent is xanthan gum, it will usually be present in an
amount corresponding to 0.1-0.5% w/w of the total weight whereas
when Avicel is used, the amount typically will lie in the range
0.6- 1.5% w/w particularly approximately 1.2% w/w. When carageenan
is used, typically this will constitute 0.5-1% w/w of the
composition. Compositions containing alginate, which has a
significant thickening effect, will, in general, contain lower
concentrations of suspending agent in order to avoid the problem of
the viscosity being so great that the composition cannot be
poured.
The suspension can contain ingredients which improve its taste, for
example sweeteners, bitter-taste maskers such as sodium chloride
and taste-masking flavours such as contramarum, flavour enhancers
such as monosodium glutamate, and flavouring agents.
Examples of sweeteners include bulk sweeteners such as sucrose,
hydrogenated glucose syrup, the sugar alcohols sorbitol and
xylitol, and sweetening agents such as sodium cyclamate, sodium
saccharin, aspartame and ammonium glycyrrhizinate.
A bulk sweetener will usually be present in an amount corresponding
to about 15-70% w/w of the total weight of the suspension, the
amount depending in part upon whether other ingredients, e.g.
alginate, are present which have a thickening effect on the
composition. For example, when sorbitol is used as the sole bulk
sweetener and no thickener (e.g. alqinate) is present, typically
the dry weight of sorbitol present is in the range 35-55% w/w of
the total weight of the suspension, for example at a concentration
of approximately 45% w/w.
When hydrogenated glucose syrup (solids content approximately 74%)
is used as the sole bulk sweetener, typically it is present as
55-70% w/w of the suspension, for example at a concentration of
approximately 65% w/w (equivalent to 49% solids). It will be
appreciated that combinations of bulk sweeteners can be used, for
example combinations of sorbitol and hydrogenated glucose syrup, or
sucrose and sorbitol.
Other excipients which can be used include humectants such as
propylene glycol and glycerol and colourants such as titanium
dioxide.
Typically the total quantity of humectant present is in the range
0-10% w/w. Thus, for example, propylene glycol and glycerol can
each be present in an amount approximating to 4% w/w.
It is preferred that the suspensions contain preservatives to
prevent microbial contamination. Examples of preservatives are the
alkylparabens, particularly propylparaben and butylparaben.
Parabens tend to be unstable at high pH values and hence most
suitably are employed when the pH is below 8.2.
Preferably the suspension contains from 1.0 to 4.5% w/w
cimetidine.
In one preferred embodiment of the invention there is provided a
composition containing 1.5-3.5% w/w of cimetidine. 35-45% w/w of
water, 35-55% of sorbitol, 0-10% w/w of a humectant which is
propylene glycol and/or glycerol, 0.6-1.5% W/w of a mixture of
sodium carboxymethyl cellulose and microcrystalline cellulose and
optionally other pharmaceutical excipients.
The compositions of this invention can optionally contain an
antacid. An antacid is a pharmaceutically acceptable basic material
of sufficient neutralising capacity to neutralise stomach acid.
Examples of antacids are aluminium hydroxide, magnesium hydroxide,
magnesium carbonate, calcium carbonate and co-dried gels for
example aluminium hydroxide-magnesium carbonate co-dried gel.
Preferably the amount of antacid is such that a unit dose contains
10-30 milliequivalents.
In a further embodiment of the invention, there is provided a
suspension of cimetidine polymorph B additionally containing
alginate.
The purpose of the alginate is to form a raft of mucilage which
floats on the contents of the stomach thereby preventing
gastro-oesophageal reflux (GORD) or reducing its symptoms. Usually
a carbonate salt such as potassium bicarbonate or sodium
bicarbonate is added. Reaction of the carbonate with the acidic
gastric juices generates carbon dioxide which aerates the alginate
raft, reducing its density and thereby enabling it more easily to
float on the stomach contents.
When bicarbonate salts are present, the suspensions are maintained
at a pH of 7.5 or more in order to prevent premature decomposition
and evolution of carbon dioxide. Typically the pH i$ maintained in
the range 7.8-8.4, for example by using a buffering agent such as a
phosphate buffer.
In order to avoid too great an increase in the viscosity of the
suspension, a low viscosity grade of alginate is used. Low
viscosity grades of alginate suitable for use in the compositions
of the present invention will generally have a viscosity of 4-10
mPa.s in 1% aqueous solution at 20.degree. C. Alginates are
polymers composed of mannuronic and guluronic acid monomer units.
The ratio of mannuronic to guluronic acids determines the
raft-forming properties of the alginate and, in general, alginates
having a high guluronic:mannuronic ratio (e.g. 70% guluronic acid)
form the strongest rafts. Alginates containing such high levels of
guluronic acid are preferably used in the compositions of the
present invention, and one such alginate is Protanal LFR 5/60.
The concentration of alginate will be chosen so as to optimise the
raft-forming ability of the suspension whilst not adversely
affecting the pourability of the suspension by increasing the
viscosity too much.
In practice, the concentration of alginate (w/w) typically is less
than 10% relative to the total weight of the suspension. Preferably
the alginate is present at a concentration of approximately 5%.
The alginate is usually present as an alkali metal salt such as
sodium alginate.
A problem which has been encountered in the preparation of
cimetidine alginate suspensions is that the cimetidine can be
oxidised to its sulphoxide. Cimetidine sulphoxide is a known
metabolite of cimetidine and whereas its presence in the suspension
does not give rise to problems of toxicity, the sulphoxide is
essentially inactive as an H.sub.2 -antagonist and thus the
oxidation of cimetidine may lead to a reduction in efficacy of the
composition.
The mechanism of sulphoxide formation is not known. The addition of
standard antioxidants such as propyl gallate and sodium sulphite
does not inhibit the formation of the sulphoxide. Moreover certain
chelating agents such as polyphosphates and trisodium citrate have
been added but have also been found to be ineffective in preventing
oxidation. However, it has now surprisingly been found that
sulphoxide formation can be significantly inhibited by the addition
of ethylenediaminetetraacetic acid (EDTA) and salts thereof.
In a preferred aspect of this invention, therefore, there is
provided a pharmaceutical suspension as hereinbefore defined
comprising cimetidine polymorph B and, additionally, alginate and
EDTA or a salt thereof. Typically the EDTA is present in an amount
from approximately 0.05% (w/w) to approximately 0.25% (w/w) of the
total weight of the suspension; particularly approximately 0.1%
(w/w). The EDTA is usually added as a salt. Particularly the
disodium salt.
In the compositions of the present invention, typically the
particle size of the cimetidine is such that in the final
suspension 80% by weight of the particles are less than 200.mu. in
size but are greater than approximately 5.mu. in size. The sizes
referred to are the apparent diameters as measured by a Malvern
3600E Laser particle Sizer (supplied by Malvern Instruments
Limited, Spring Lane, Worcester, U.K.).
The compositions of the present invention can be prepared by mixing
the cimetidine polymorph B with the suspending agent, and any other
ingredients to be included, to form a suspension.
The cimetidine polymorph B can be prepared by forming a solution of
cimetidine acetate in aqueous isopropanol (10% isopropanol),
clarifying bY filtration and basifying with aqueous ammonia (10%
excess) as described in Appendix A. The mixture is then stirred to
allow the polymorph B to crystallise completely, then the product
is isolated by filtration, washed well with water and dried to
constant weight.
The invention is illustrated but in no way limited by the following
examples. In the examples, all references to cimetidine refer to
the B polymorph unless otherwise stated.
EXAMPLE 1
Cimetidine Suspension (200 mg in 10 ml)
______________________________________ UNIT QTY DOSE INGREDIENTS
(g) mg/10 ml ______________________________________ Cimetidine Base
(B Polymorph) 120.0 200 Avicel RC591 90.0 150 Water 1500.0 2500
Propylene Glycol 300.0 500 Glycerol 300.0 500 Butylparaben 6.0 10
Propylparaben 3.0 5 Sodium Saccharin 2.4 4 Vanilla (Firmenich
54.286C) 3.0 5 Cream (FDO FC 900772) 6.0 10 Titanium Dioxide 50% in
Glycerol 24.0 40 Sorbitol 70% in water* 4940.0 8234
______________________________________ *Sorbitol 3460 g, Water 1480
g.
PROCESS
The Avicel is dispersed in demineralised water using a low shear
propeller mixer and the resulting dispersion is passed through a
premier colloid mill (premier Colloid Mills Ltd., Walton-on Thames,
Surrey, U.K.) on high speed at 25.mu. gap. The Avicel high shear
dispersion is mixed with 3.6 kg of the sorbitol 70% solution and to
the mixture is added the glycerol followed by a solution of the
parabens in propylene glycol. The flavourings and the titanium
dioxide paste are then added with stirring to give a homogenous
mixture. Cimetidine is then added followed by the remainder of the
sorbitol to give a total volume of 6 liters. The batch is then
passed through a colloid mill on low speed set to the smallest
possible gap (approx 25.mu.) such that the milling process does not
cause the temperature of the milled material to exceed 35.degree.
C. The pH of the resulting suspension is approximately 7.8.
EXAMPLE 2
Cimetidine Suspension (200 mg in 5 ml)
This has a similar composition to that described in Example 1
except that the quantity of cimetidine is doubled
EXAMPLE 3
Cimetidine Suspension in Hydrogenated Glucose Syrup
This has a composition analogous to that described in Example 2
except that instead of sorbitol 70%, an equivalent volume of
hydrogenated glucose syrup (74% solids) is used as the vehicle.
EXAMPLE 4
Determination of the viscosities of the formulations of Examples 1
to 3, 6 and 8
The viscosities of the compositions of Examples 1 to 3, 6 and 8
were determined using a Rheomat 30 Rheometer supplied by Contraves
of Switzerland. The measurements were conducted at 27.degree. C.
and the results are shown in Table 2.
TABLE 2 ______________________________________ Apparent Viscosity
(.eta.a) (mPa .multidot. s) Shear Rate Examples (sec..sup. -1) 1
and 2 Example 3 Example 6 Example 8
______________________________________ 0.7 700 1000 3400 1000 7 400
800 1000 500 70 200 300 500 200 700 100 200 300 100
______________________________________
EXAMPLE 5
Comparative Stabilities of Suspensions containing Polymorph A and
Suspensions containing Polymorph B
(i) Compositions as described in Example 1 were subjected to
isothermal storage for one year at temperatures of 4.degree.,
22.degree., 30.degree. and 40.degree. C. Microscopic examination
after this time indicated that no crystal growth had occurred.
The composition of Example 1 was also subjected to 50 thermal
cycles between 10.degree. and 30.degree. C. No crystal growth was
detected following this test.
(ii) Compositions identical to :hose described in Example 1, except
that cimetidine polYmorph A was used instead of cimetidine
polymorph B, were also subjected to stability tests. The median
particle size in the freshly prepared suspensions was approximately
40.mu..
After 5 months at room temperature filaments 750.mu. in length were
observed upon microscopic examination.
At ten months filaments up to 2.5 mm were observed along with
filamentous clusters up to 1 mm in length.
Upon storage at 30.degree. C. for 3 days, filaments up to 2.5 mm in
length were observed and after storage at 40.degree. C. for 3 days
a large filamentous aggregate of 4 mm overall length was
detected.
After thermal cycling, 10.degree.-30.degree. C., 9 cycles, numerous
feather-like clusters up to 800.mu. long and 200.mu. wide were
formed. One feather-like aggregate of 1.8 mm length was
detected.
EXAMPLE 6
100 Mg Cimetidine/Sodium Alginate Suspension
______________________________________ UNIT DOSE QUANTITY
INGREDIENTS (g/100 ml) ______________________________________
Cimetidine Base 2.0 Sodium Alginate (Protanal LFR 5/60) 5.0
Potassium Bicarbonate 3.18 Propylene Glycol 5.0 Glycerol 5.0 Avicel
CL-611 (Microcrystalline cellulose 0.2 and sodium
carboxymethylcellulose) Sorbitol Solution BP (70% w/w) 22.0
Hydrogenated Glucose Syrup (Lycasin 80/55) 4.0 Butylparaben 0.1
Propylparaben 0.05 Ethylenediaminetetraacetic acid 0.1 (disodium
salt) Sodium dihydrogen orthophosphate 0.31 dihydrate Di-Sodium
hydrogen orthophosphate 0.475 dodecahydrate Sodium Saccharin 0.2
Passion Fruit Flavour 0.01 Peppermint Flavour 0.02 Titanium Dioxide
in 50% Glycerol 0.8 Demineralised Water to 100 ml
______________________________________
PROCESS
The hydroxybenzoates were dissolved in warm propylene glycol and to
the resulting solution was added the glycerol. After the solution
had cooled to room temperature, the cimetidine was added with
stirring to give a smooth slurry.
A sodium alginate mixture was prepared by dissolving the disodium
edetate in demineralised water and then dispersing the sodium
alginate in the solution using a high shear homogeniser.
The cimetidine slurry sorbitol solution, hydrogenated glucose syrup
and sodium alginate mixture were added to a dispersion of the
Avicel in demineralised water and the resulting mixture was stirred
until homogenous. The remaining ingredients were added, additional
demineralised water being added as necessary to give the correct
volume. Finally, the suspension was passed through a colloid mill
set at low speed as described in Example 1.
EXAMPLE 7
200 mg/5 ml Cimetidine/Magnesium hydroxide/Aluminium hydroxide
Suspension
______________________________________ g/100 ml % (w/w)
______________________________________ Cimetidine 4 3.31 Magnesium
hydroxide 4 3.31 Aluminium hydroxide (as Al.sub.2 O.sub.3) 2.4 1.98
Xanthan 0.3 0.25 Propylparaben 0.05 0.041 Butylparaben 0.10 0.083
Propylene glycol 5.0 4.13 Glycerol 2.0 1.65 Sorbitol (70%) 75 62.0
Water to 100 ml. ______________________________________
EXAMPLE 8
100 mg/5 ml Cimetidine/Magnesium hydroxide/Aluminium hydroxide
Suspension
______________________________________ g/100 ml % (w/w)
______________________________________ Cimetidine 2 1.65 Magnesium
hydroxide 4 3.31 Aluminium hydroxide (as Al.sub.2 O.sub.3) 2.4 1.98
Xanthan 0.3 0.25 Propylparaben 0.05 0.041 Butylparaben 0.10 0.083
Mint Flavouring 0.10 0.083 Propylene Glycol 5.0 4.13 Glycerol 2.0
1.65 Sucrose 35 28.9 Sorbitol (70%) 25 20.7 Water to 100 ml.
______________________________________
EXAMPLE 9
100 mg/5 ml Cimetidine/Calcium Carbonate Suspension
______________________________________ g/100 ml % (w/w)
______________________________________ Cimetidine 2 1.51 Calcium
carbonate 11.7 8.86 Avicel RC591 1.5 1.14 Propylparaben 0.05 0.038
Butylparaben 0.10 0.076 Sodium saccharin 0.04 0.030 Vanilla 0.05
0.038 Flavours Cream 0.10 0.076 Titanium dioxide (50%) 0.4 0.30
Propylene glycol 5.0 3.78 Glycerol 5.0 3.78 Water 25 18.93 Lycasin
(hydrogenated glucose syrup) to 100 ml 61.42
______________________________________
EXAMPLE 10
Cimetidine/Calcium carbonate/Magnesium hydroxide Suspensions
______________________________________ g/100 ml (w/w)
______________________________________ Cimetidine 2 1.5 Calcium
Carbonate 10 7.52 Magnesium hydroxide 1 0.75 Avicel RC591 1.5 1.13
Propylparaben 0.05 0.038 Butylparaben 0.10 0.075 Sodium Saccharin
0.04 0.03 Vanilla 0.05 0.038 Flavours Cream 0.10 0.075 Titanium
dioxide (50%) 0.4 0.30 Propylene glycol 5.0 3.76 Glycerol 5.0 3.76
Water 25 18.79 Lycasin (hydrogenated glucose syrup) to 100 ml 62.24
______________________________________
APPENDIX A
Preparation of Cimetidine Polymorph B
To a stirred suspension of 252 grams of cimetidine polymorph A in
2.0 liters of water and 250 ml of isopropanol was added a solution
containing 60 grams of acetic acid in 125 ml water. The mixture was
stirred and the resulting solution was clarified by filtration. To
the resulting clear solution was added with agitation a solution
containing 68 ml of concentrated ammonia (27% w/w) in 125 ml of
water. Following precipitation of the cimetidine base, the mixture
was heated to 40.degree.-45.degree. C., and held there for 24
hours. The appropriate in-process checks* after this time indicated
that the solid was completely form "B". The mixture was cooled, the
product isolated by filtration, and washed well with water. The
solid was dried at 60.degree. C. to yield 240 grams (95%) of
crystalline cimetidine "B" having a melting point of
142.5.degree.-144.degree. C. * An appropriate process check is to
obtain an infra-red spectrum of the product and calculate the ratio
of the peak heights of the absorbance bands at 1004 and 993
cm.sup.-1. The concentration of polymorph C is then determined by
reference to a calibration curve obtained by plotting the peak
ratios for various standard mixtures of polymorph C and polymorph
B.
The above-mentioned process for preparing cimetidine polymorph B is
also disclosed and is claimed in a co-pending European patent
Application which derives priority from British patent Application
No. 8618846 filed on 1st August 1986. The term "polymorph B" as
used hereinabove includes a reference to crystalline cimetidine
prepared according to the said process.
* * * * *